When solid phase peptide synthesis was first introduced by Bruce Merrifield.sup.1 it was performed on a support of 2% cross linked polystyrene allowing the preparation of a pentapetide by a batchwise synthesis protocol, This invention formed the basis of a technique, which has since been subjected to continuous refinement. With the synthesis of longer peptides it soon became apparent that the cross linking of the resin had to be optimized. The best results were obtained with the 1% Gross linked resin still used in the batch synthesis today.sup.2. A more polar dimethyl acrylamide resin suitable for peptide synthesis in polar solvents like DMF was developed in Sheppards laboratory.sup.3.
With the introduction of Fmoc-based solid phase synthesis.sup.4,5 the much more efficient continuous flow process became a realistic alternative to the batch method. The available batch resins were however not flow stable and collapsed after a few synthesis cycles. It was well established that increased cross linking while increasing the stability of the resin would not lead to useful properties for peptide synthesis. The first flow stable synthesis resin was obtained by polymerization of the soft polydimethyl acrylamide gel inside a solid matrix of supporting kieselguhr.sup.6. This ingenious invention allowed the packing of columns, which were completely flow stable throughout the synthesis. The principle was refined by replacing the irregular kieselguhr with a more regular rigid 50% cross linked polystyrene sponge containing a grafted polydimethyl acrylamide gel.sup.7.
At the same time a technique was developed for grafting polyethylene glycol on to a 1% crosslinked polystyrene.sup.8. The resulting resins were monodisperse, spherical and, more importantly, flow stable. A more controlled grafting by direct substitution of the functional groups in the polystyrene with modified polyethylene glycol carrying an amino group has also been described.sup.9. Polystyrene grafted to films of polyethylene has been used for synthesis of peptides under nonpolar conditions.sup.10 and polyhydroxypropyl acrylate coated polypropylene.sup.11 and the natural polymer, cotton, has shown some promise as supports under polar conditions.sup.12.
A preparation of a polymer with short crosslinking PEG chains (n=6) was attempted by inverse suspension polymerization of polyethylene glycol methacrylate macromonomers.sup.13 ; but with the high PEG content (60% crosslinker) the polymer became semicrystalline already during the polymerization reaction. The described polymer of short chain PEG crosslinked by means of ester linkages.sup.13 was not suited for peptide synthesis.